ABSTRACT Endometriosis affects 6-11% of premenopausal women, causing pain, infertility, and billions of dollars in U.S. health care related costs annually. With a poorly understood etiology, endometriosis is characterized by hormonally responsive endometrial implants outside the uterus. Evidence from experimental and human studies indicate that endocrine disrupting chemicals, to which humans are nearly ubiquitously exposed, may play a role in endometriosis etiology and severity. We propose to measure nine perfluoroalkyl substances (PFASs) and 53 persistent organic pollutants (POPs) to which the population is broadly exposed, in eutopic (healthy uterine tissue) and ectopic (endometriosis implants) endometrial tissue. The literature is limited in that there are no studies of endometriosis incidence and severity in relation to PFASs, POPs, and their mixtures measured in uterine tissue. This study leverages a unique biorepository collected from the operative cohort of the Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO) Study, an NICHD study which enrolled 495 women aged 18-44 from 14 clinical centers in California and Utah prior to laparoscopic surgery. We will determine: 1) whether higher levels of PFASs, POPs, and their mixtures in eutopic endometrial tissue are associated with incident endometriosis and 2) how these exposures in ectopic endometrial tissue are associated with endometriosis severity; 3) whether mixtures of PFASs and POPs across serum, adipose tissue, and eutopic endometrial tissue, are associated with endometriosis incidence; and finally, 4) recognizing the infeasibility of most epidemiologic studies of gynecologic disease to obtain endometrial tissue, we will develop a model to predict eutopic endometrial dose from serum levels of PFAS and POP exposure. This study will provide critical data on PFASs and POPs, which will advance scientific understanding and inform policy makers.